Many cancer therapeutics rely on initiation of apoptosis. Problems seen with cancer therapeutics include drug resistance and toxicity (arising from insufficient selectivity). The selective induction of apoptosis in tumour cells versus normal cells is a key goal of cancer therapeutic drug discovery. One drug designed to selectively induce apoptosis is the isoquinoline carboxamide PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide). PK11195 does, however, have limitations in a clinical setting, for example in terms of poor solubility and dosage levels required.
Previously, PK11195 was thought to induce apoptosis by interaction with the peripheral benzodiazepine receptor (PBR). The PBR has been implicated in the regulation of the permeability transition pore complex (PTPC), opening of which results in mitochondrial membrane depolarisation, causing the release of cytochrome c and initiating a series of steps that leads to cell death by apoptosis.
More recently, it has been reported that functions have been erroneously ascribed to the PBR in the cellular effects of PK11195. Instead, it has been determined that PK11195 acts by a PBR independent intracellular mechanism involving intra-mitochondrial superoxide (WO 2006/018625, the contents of which are incorporated herein by reference). The mechanism of action ascribed to PK11195 in WO 2006/018625, involves the internalisation of PK11195 within mitochondria, enzymatic action of NADPH oxidase on PK11195 to remove a chlorine atom from PK11195 and replacement of the removed chlorine atom with an oxygen atom, thereby turning PK11195 into a reactive oxygen species (ROS) by superoxidation. The reactive oxygen species affects the redox sensitive mitochondrial membrane permeability transition pore complex (PTPC), resulting in mitochondrial membrane depolarisation, which causes the release of cytochrome c and initiates a series of steps leading to cell death by apoptosis.
Determination of this mechanism of action provides an important route for selectively inducing apoptosis of tumour cells, useful for example in treating cancer, in particular NADPH oxidase-positive cancers. The object of the invention is therefore to provide compounds which are capable of inducing apoptosis by the mechanism of action described above, with improved potency, efficacy and drugability. It has now been determined that certain classes of compounds show good efficacy in inducing cell apoptosis by the intra-mitochondrial superoxidation mechanism described above.